Transplant Trial Watch

To keep the transplantation community informed about recently published level 1 evidence in organ transplantation ESOT and the Centre for Evidence in Transplantation have developed the Transplant Trial Watch. The Transplant Trial Watch is a monthly overview of 10 new randomised controlled trials (RCTs) and systematic reviews. This page


Aims
This post hoc analysis of the TRANSFORM study aimed to compare the effect of everolimus (EVR) and reduced calcineurin inhibitor (rCNI) versus standard triple therapy on cardiovascular disease (CVD) outcomes in de novo kidney transplant patients.

Interventions
Participants in the TRANSFORM trial were randomised to either the EVR + rCNI group or the mycophenolic acid (MPA) + standard-exposure CNI (sCNI) group.
Participants 2026 de novo kidney transplant recipients.

Outcomes
The main outcomes of interest were the incidence of major adverse cardiac event (MACE), cardiac deaths, time-to-event analysis of MACE, CVD risk factors and levels of metabolic parameters.

CET Conclusion
Everolimus is known to worsen post-transplant dyslipidaemia, but it is not clear that this results in poorer cardiovascular outcomes. This post hoc analysis of the TRANSFORM study, which compared outcomes in kidney transplant patients on standard immunosuppressive therapy vs. a everolimus/reduced tacrolimus regimen, compared the rate of major adverse cardiac events (MACE) between the two groups over a 2 year follow up period. Over 2,000 patients were included in the analysis. Although lipid levels were increased in the everolimus group as expected, the rate of MACEs were not significantly different between the two groups. The authors speculated whether this could be due to cardio-protective effects due to everolimus, which had previously been demonstrated in preclinical studies, and which offset the lipid dysregulation effects. With the potential to reduce posttransplant viral infections, these findings provide further evidence to support everolimus based regimens as a viable alternative to current immunotherapy standard of care.

Funding Source
Industry funded.

Aims
The investigators aim to assess if switching from mycophenolate or azathioprine to sirolimus following first cytomegalovirus (CMV) infection post-transplant reduces recurrence rate of CMV infections.

Interventions
Once randomised the intervention group were abruptly converted from antimetabolite (mycophenolate sodium 720 mg twice daily or azathioprine 2 mg/kg once daily) to sirolimus (5-8 ng/mL), tacrolimus was continued, but the maintained concentrations were lowered to 3-5 ng/mL. The control group continued tacrolimus (5-10 ng/mL) and their antiproliferative agent.
Participants 72 adult kidney transplant recipients who had a treated CMV infection within the first 6 months after transplant.

Outcomes
The primary endpoint was the incidence of recurrent CMV infection within 12 months following randomisation. The secondary endpoints were: Incidence of de novo DSA, kidney function, proteinuria, acute rejection, graft loss and death.

Follow-Up
Participants were followed-up for 12 months.

CET Conclusion
This small prospective unblinded randomised control trial demonstrates that conversion to sirolimus form antimetabolite following initial CMV infection has a significant effect to reduce recurrent infection. Within the sirolimus cohort no episodes of CMV infection or disease occurred within the study period. Whereas the control group had a recurrence rate of 43%. All the patients in this study are high risk for CMV with all recipients being CMV positive pre-operative, but received no pre-emptive pharmacological treatment, simply weekly blood monitoring. Upon CMV infection/ disease intravenous ganciclovir was commenced and once treated the antimetabolite switch to sirolimus and the study period commenced. Within the study group they saw no significant difference in biopsy confirmed acute rejection, de novo DSA, proteinuria, graft survival or death. The generalisability of these findings is limited due to the strict inclusion criteria, within their study period they randomised 72 patients out of a total of 1,309 with a first-treated CMV infection/disease, all of whom were lowimmunological risk. The patient cohort and small sample size limits safety and efficacy conclusion as well as conclusion in broader recipient populations, such as D+/R−. While there is insufficient evidence to change current practice it sits along side other trials, some of which multi-centre and larger supporting mTORi in improving CMV related outcomes, although often with higher discontinuation rates.

Data Analysis
Strict intention-to-treat analysis.

Allocation Concealment
Yes.

Funding Source
Industry funded.

CLINICAL IMPACT SUMMARY
Pre-emptive treatment of CMV after renal transplantation is associated with a considerable risk of later CMV infection recurrence, and further changes to immune suppression and